Neurotransmitter serotonin or 5-Hydroxytryptamine (5-HT) is abundantly distributed in the central nervous system, including hippocampus and frontal cortex. 5-HT receptors are a family of G-protein coupled receptors, characterized with 7-transmembrane helices and presently have fourteen known receptor subtypes, some of which exist as multiple splice variants [D. L. Murphy, A. M. Andrews, C. H. Wichems, Q. Li, M. Tohda and B. Greenberg, J. Clin. Psychiatry, 1998, 59 (suppl. 15), 4]. 5-HT influences a number of physiological functions and is implicated in a large number of central nervous system disorders and neurodegenerative diseases [W. E. Childers, Jr. and A. J. Robichaud, Ann. Rep. Med. Chem. 2005, 40, 17].
5-HT2B receptors are widely distributed in mammalian peripheral tissues including lung, heart, pancreas, spleen, prostate, liver, vascular and skeletal muscle, adipose tissue, intestine, ovary, uterus, testis, and in the central nervous system (CNS) including brain and cereberal cortex. 5-HT2B receptors are present in many vascular beds and have been localized to both vascular smooth muscle and vascular endothelial cells in humans. The receptor was characterized in the rat gastric (fundus) smooth muscle cells initially as the receptor responsible mediating serotonin-induced contraction in this tissue.
5-HT2B receptor antagonists have the potential to be selective for diseased pulmonary trachea, thymus, thyroid, salivary gland vasculature (i.e., vessels affected by hypoxic conditions) compared to normal pulmonary and systemic vessels. Due to this selectivity, 5-HT2B antagonists offer a possible therapeutic advantage over the available agents for the treatment of pulmonary arterial hypertension and related disease of the lung and vascular system.
Pulmonary hypertension (PH) is a progressive, debilitating and often fatal disease that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. PH is estimated to affect 100,000 people worldwide. Current treatments include systemically administered intravenous and subcutaneous prostacyclin analogs and orally active endothelin receptor antagonists, which mainly cause pulmonary arterial dilation to relieve symptoms. There is only one approved orally active agent for PH available for patients, a non-specific endothelin A and B receptor antagonist which requires liver toxicity monitoring.
The novel compounds of formula I have 5-HT2B receptor antagonist activity and have applications as safer and effective therapeutic drugs for the treatment of pulmonary arterial hypertension, resistant hypertension, hypertension, congestive heart failure and erectile dysfunction, Alzheimer's disease, and age-related cognitive and memory dysfunction and cognitive and memory impairment associated with schizophrenia. These compounds may also have applications in the treatment of gastrointestinal disorders including irritable bowel syndrome, Crohn's disease, gastroesophageal reflux disease, emesis, nausea, vomiting, prokinesia, non-ulcer dyspepcia, anxiety, depression, pain, migraine, urinary incontinence, arterial fibrillation, arrhythmia, ischemic stroke, gastric emptying disorders, gastritis, gastrointestinal disorders, feeding disorders, obesity, anorexia, constipation, constipation, and respiratory depression.